Peptide-conjugated phage-mimicking nanoparticles exhibit potent antibacterial action against Streptococcus pyogenes in murine wound infection models

The development of antibiotic resistance and the resulting emergence of multidrug-resistant bacteria has become one of the main threats in the public health system, commonly leading to nosocomial infections. Many researchers have turned their focus to developing alternative classes of antibacterial systems based on various nanomaterials. We have developed an antibiotic-free nanoparticle system, inspired by naturally occurring bacteriophages, to fight antibiotic-resistant bacteria. Our phage-mimicking nanoparticles (PhaNPs) display structural mimicry of protein-turret distribution on the head structure of bacteriophages. By mimicking phages, we are able to take advantage of their evolutionary constant shape and their high antibacterial activity while avoiding immune reactions of the human body, potentially caused by phages. We describe the synthesis of hierarchically arranged core-shell nanoparticles, with a silica core conjugated with silver-coated gold nanospheres. Improving on our previous design, we have chemisorbed the synthetic antimicrobial peptide Syn-larvacin 71 on the PhaNP surface which further increases the antibacterial activity of the nanoparticles (PhaNP@Syn71). The antibacterial effect of the PhaNP@Syn71 was tested in vitro and in vivo against Streptococcus pyogenes, a causative agent for strep throat, impetigo, and more invasive diseases. In vitro results showed delayed growth as well as inhibition of bacterial growth (up to 99%). Cytocompatibility testing on HaCaT human skin keratinocytes showed minimal cytotoxicity of PhaNP@Syn71, being comparable to the vehicle cytotoxicity levels even at higher concentrations, thus, proving that our design is biocompatible with human cells. Studies on a mouse wound infection model exhibited high biocompatibility in in vivo settings while showing immediate stabilization of the wound infection following the first dose of PhaNP@Syn71. Our results suggest the strong utility of antimicrobial peptide-conjugated phage-mimicking nanoparticles as a highly effective antibacterial system that can combat a clinically relevant bacterial pathogen.